Voriconazole, (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol having the structure of formula (I), is an antifungal drug used for preventing or treating fungal infection, e.g., human local fungal infection caused by candida, trichophyton, microspourum or epidemophyton; mucosal infection, by candida albicans (e.g., thrush and candidiasis); and whole body fungal infection, by aspergilus.

Voriconazole has two asymetric carbon atoms, and therefore, 4 stereoisomers, enantiomers of two diastereomeric pairs are involved in the preparation thereof which is generally conducted by a) separating an enantiomeric pair having (2R,3S) and (2S,3R) configurations; and then b) separating the (2R,3S)-stereoisomer using an optically active acid (e.g., R-(−)-10-camphosulfonic acid). The structural specificity and instability under a basic condition make the stereoselective synthesis of voriconazole difficult.
To date, only two methods for preparing voriconazole have been reported. One is based on a coupling reaction using an organic lithium salt, and the other, on Reformatsky-type coupling reaction.
For example, Korean Patent No. 1993-0011039 and European Patent No. 0,440,372 disclose a method shown in Reaction Scheme A for preparing the desired enantiomeric pair by a) adding an organic lithium derivative of 4-chloro-6-ethyl-5-fluoropyrimidine to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone at −70° C.˜−50° C. to obtain an enantiomer mixture; and b) separating the desired enantiomer by chromatography.

However, this coupling reaction using a strong base such as LDA or NaHMDS produces (2R,3S)/(2S,3R) and (2R,3R)/(2S,3S) diastereomers in a mole ratio of 1.1:1 without stereoselectivity, and the desired (2R,3S)/(2S,3R)-enantiomeric pair is isolated in a yield of only 12˜25%. Further, the lithium salt used in the reaction is difficult to be applied to mass production because of the required anhydrous condition at −78° C.
PCT Publication No. WO 2006/065726 discloses a method shown in Reaction Scheme B for preparing the desired enantiomeric pair by repeating the procedure of Reaction Scheme A except for using a different solvent.

However, despite the merit of this reaction which allows the separation of the desired enantiomeric pair by crystallization, it is hampered by the same problems associated with Reaction Scheme A and the yield of the desired enantiomeric pair is only 26%.
In order to solve the problems, as shown in Reaction Scheme C, Korean Patent Publication No. 1999-0036174 and U.S. Pat. No. 6,586,594 B1 disclose a method for preparing voriconazole by conducting Reformatsky-type reaction to enhance the stereoselectivity and yield, and then reductively removing the chlorine substituent in the presence of a palladium catalyst.

In this reaction, the (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pairs were formed in a mole ratio of 9:1, and the yield of the isolated voriconazole hydrochloride was as high as 65%. However, the pyrimidine derivative used as a starting material is difficult to remove when remains unreacted, which leads to the lowering of the product purity.
Further, the literature ([Organic Process Research & Development 2001, 5, 28-36], Pfizer Inc.) teaches that the chlorine substituent of the pyrimidine derivative adversely influences the coupling reaction pattern as shown in Reaction Scheme D and Table 1.

TABLE 1Reformatsky-type reaction of compounds (VI, VII) and (IV)CompoundCompoundUnreactedDebrominatedCompoundCompoundPyrimidine(VIII) (%)(IX) (%)pyrimidine (%)pyrimidine (%)(X) (%)(XI) (%)Compound47.524.00.0154.39.2(VI)Compound5.34.68.5280.051.6(VII)
Example 1 of Korean Patent Publication No. 1999-0036174 (see Reaction Scheme C) shows that the (2R,3S)/(2S,3R)- and (2R,3R)/(2S,3S)-enantiomeric pairs were obtained in a mole ratio of 10:1, but the product mixture contained unreacted compound of formula (IV) (7%) and unknown byproduct suspected to be the compound of formula (XI) (14%). Thus, the procedure of Reaction Scheme C gives an impure product mixture, the isolation of the desired product by recrystallization giving only a yield of 40˜45%.